Please see Bibliography of References for a list of abstracts, manuscripts and posters.
Draisma, Bemelmans R, van der Hoeven JG, Spronk P, Pickkers P. Int Care Med. 2008;34(Supp 1):S103. Abstract 0391.
Introduction: Changes in microcirculation and mitochondrial dysfunction appear to be key mechanisms in sepsis, since they can lead to regional mismatch of oxygen supply and demand. Lipopolysaccharide (LPS, endotoxin) can be used to induce endotoxemia as a model of inflammation in humans, but the effects on microcirculatory perfusion have not been tested before. We were particularly interested in microcirculatory changes during repeated administrations of LPS when endotoxin tolerance developed. The aim of our study was to compare 3 methods to investigate microcirculation and vascular reactivity during endotoxemia and endotoxin tolerance.
Methods: Endotoxin tolerance was induced in 9 volunteers by intravenous injection of 2ng/kg/day lipopolysaccharide on 5 consecutive days. Microcirculation and vascular reactivity was monitored before (t=0) and after (t=2 and 4 hrs) LPS administrations on day 1 and 5. Near Infrared Spectroscopy (NIRS) measured thenar muscle tissue saturation before, during and after arterial occlusion (ischemia) was induced by inflating a cuff above the elbow to 50mmHg above systolic blood pressure for 90 seconds. Orthogonal Polarization Spectral imaging (OPS) measured microvascular perfusion sublingually using side stream darkfield imaging in small, medium and large sized microvessels. Forearm blood flow (FBF) was measured by strain-gauge plethysmography during local intra-arterially infusion of endothelial-dependent vasodilatory acetylcholine.
Results: Endotoxin tolerance developed during 5 consecutive days of LPS administration as demonstrated by the attenuated release of pro-inflammatory cytokines and absence of symptoms and fever on the fifth day. Both NIRS and OPS did not demonstrate changes in microcirculation during endotoxemia or endotoxin tolerance in vivo. FBF measurements showed an acetylcholine dose-dependent attenuation (from 5.7±2.6 to 2.6±2.0) after the first administration of LPS (p=0.01), but not after acetylcholine stimulation when tolerance was present (from 6.1±2.1 to 5.8±3.7) on day 5(p=0.25).
Conclusion: In this human endotoxin tolerance model, no significant effect of repeated LPS administrations on microcirculatory perfusion could be observed using NIRS (thenar muscle) and OPS (sublingual). The forearm blood flow however, was attenuated after the first administration of LPS, indicating an endothelial dysfunction in endotoxemia in vivo. This attenuated response to acetylcholine was not present after the fifth administration of LPS, which may indicate that tolerance is also present at the levels of the endothelium.